The interaction of metal complexes with DNA and RNA will be studied in order to probe primary and tertiary structure and to monitor drug activity, especially growth inhibition of cancerous vs. normal cells. Specificity of metal binding will be effected using class b metal complexes (RHgX, R2PbX2, R2TlX, etc.) and thiolated nucleotides. Conditions for metal binding will be optimized using E. coli tRNAs containing S4U on which preliminary work has already provided several valuable leads. A long term goal is to incorporate thiolated nucleotides into RNA and DNA, label them with heavy metals, and sequence for labeled nucleotide using electron microscopy. Conformational changes at the labeled S4U sites of E. coli tRNAs will be monitored by fluorescence and nmr spectroscopy. The intercalation of terpyridyl palladium and platinum complexes into DNA and tRNA, recently discovered in our laboratory, will be extended to include lanthanide shift reagents. These probes will be applied to RNA and DNA structural problems. The biological activity of the metal (especially platinum) intercalation reagents will be assayed in tissue culture experiments. Preliminary studies have shown (terpy)PtCl2 to be a highly effective growth inhibitor, selective for cancer vs. normal cells. The proposed new studies should enable correlation of the chemistry and molecular biology of metal intercalation complexes with their drug activity.